Epidermal growth factor (EGF), acting through its receptor EGFR, is a mitogen and survival factor for keratinocytes and other epithelial cells (Rheinwald et al. Nature, 1997: 265:421; Rodeck et al. J. Cell Science, 1997; 110:113). It is crucial for the normal development and physiology of the epidermis. Inhibition of EGFR can result in abnormal proliferation, migration and premature differentiation of basal keratinocytes as demonstrated by upregulated p27KIP1, KRT1 and STAT3 in the basal layer, and consequent disruption of the integrity of the skin with the recruitment of inflammatory cells (Jost et al. Eur. J. Dermatol. 2000; 10:505-510; Lacouture, Nat. Rev. Cancer 2006; 6:803-812).
Agents that inhibit EGFR have been shown to be active antitumor agents against a variety of solid tumors including but not limited to colorectal carcinoma, non-small cell lung cancer, head and neck cancer and malignant gliomas (Conen et al., 2003; Lage et a!., 2003; Lorusso, 2003; Vanhoefer et al., 2004). Clinical benefit, defined as relief of symptoms or prolongation of survival, has been so far demonstrated with the anti-EGFR antibody cetuximab (Erbitux®) and the EGFR tyrosine kinase (TK) inhibitors gefitinib (Iressa®) and erlotinib (Tarceva®).
In addition, EGFR inhibitors are increasingly being used in a range of tumor types in combination with standard therapies in an attempt to improve outcome. In 2006, results of a randomized phase III study demonstrated that the addition of the EGFR-targeted IgG1 mAb, cetuximab, to radiotherapy resulted in statistically significant and clinically meaningful improvements in the duration of locoregional control and median overall survival versus radiotherapy alone in the treatment of locoregionally advanced squamous cell carcinoma of the head and neck (Bonner al. N. Engl. J. Med. 2006; 354:567-578).
Although EGFR inhibitors do not cause life threatening toxicities, their use can be associated with the development of skin reactions, including a macular, papular, pustular rash, commonly referred to as acne-like rash (or folliculitis); xerosis; fissures; telangiectasia; hyperpigmentation; and hair and nail changes (Segaert et al. Ann. Oncol. 2005; 16:1425-1433). In addition, inflammation is commonly found in the epidermal-dermal junction, accompanied by neutrophilic infiltration and damage to the hair follicles.
The most common skin reaction, the acne-like rash which occurs in 60-70% of patients, is generally distributed in areas rich with sebaceous glands, such as the face, neck and retroauricular area, the shoulders, the upper trunk and the scalp. Main symptoms caused by the skin rash, itching, dryness, and secondary infection, cause discomfort and unfavorable cosmetic changes in many cases. The occurrence and intensity of the rash are clearly dose-related and the median time of occurrence is 10 days after initiation of therapy and peaks after 2-3 weeks. In some cases, the rash can be delayed, and in others flares can occur at each subsequent, administration of the EGFR inhibitor. In addition, abnormalities in hair growth especially the scalp and eyelashes have been reported in approximately 20% of patients, and periungual inflammation with tenderness in about 15% (Lacouture, Nat. Rev. Cancer, 2006; 6:803-812). About 10% of patients discontinue therapy due to skin toxicity.
There is growing evidence that the skin rash is a surrogate indicator of antitumor efficacy and clinical benefit of anti-EGFR therapy (Cohen et al. J. Clin. Oncol., 2003; 21:1980-1987). Accordingly, increasing dosing of anti-EGFR agents to cause a skin rash may become a common practice and the effective treatment of the skin rash is also becoming of increasing importance. Topical or systemic antibiotics, anti-inflammatory agents, retinoids, topical lubricants, and other types of remedies have been tried in an empirical fashion with poor or inconsistent results. More recently, the topical application of menadione (vitamin K3), an EGFR phosphatase inhibitor, was shown to restore EGFR-mediated signaling in human skin secondary to systemic administration of the EGFR inhibitors, erlotinib and cetuximab (Ling et al. WO 2006/113479).
Accordingly, there is a need for effective topical formulations for the treatment and/or prevention of this EGFR-mediated skin conditions including epithelial toxicity associated with anti-EGFR therapy, a condition that is expected to affect more than 150,000 individuals each year in the USA alone.